The present invention is directed to methods for chemically synthesizing compounds containing a hydronaphthalene ring structure. It encompasses the compounds made by the methods, pharmaceutical preparations containing the compounds, and methods for treating patients using these pharmaceutical preparations.
The hydronaphthalene structure can be found in many natural products and pharmaceutical agents. These include homochelidonine (structure 1 below; Slavik, J.; et al., Collect. Czech. Chem. Commun. 30:3697 (1965); Spath, E., et al., Ber., 64:1123 (1931); Bersch, H. W., Arch. Pharm. (Weinheim, Ger.), 2914:91 (1958)) an alkaloid isolated from Chelidonium plants, dihydrexidine (structure 2 below; Snyder, S. E., J. Med. Chem., 38:2395 (1995)) which shows antiparkinsonian character, etoposide (structure 3 below; Kamal, A., et al., Tetrahedron Lett. 37:3359 (1996)) which is used in the treatment of various cancers, and SF-2315B (structure 4 below; Kim, K., et al., J. Org. Chem. 60:6866 (1995)) which is a viral reverse transcriptase inhibitor. In addition, CNS agents, immunoregulatory agents and antibiotics contain variations on this framework (Perrone. R., et al., J. Med. Chem. 38:942 (1995)). 
Given the large number of pharmaceutically useful compounds which contain this core skeleton, new methodology which produces functionalized hydronaphthatene skeletons (structure 1) would clearly be of value. 
Previous work on oxabicyclic ring opening reactions led to a catalytic enantioselective route to dihydronaphthol (Lautens, M., et al., Tetrahedron 54:1107 (1998)) which was a key step in the total synthesis of sertraline (Lautens, M., et al., J. Org. Chem. 63:5276 (1997)). However, little is known about the ring opening of oxabenzonorbornadiene or similar compounds with the incorporation of nucleophiles during the ring opening step. Duan and Chen developed a method of introducing aryl groups by using catalytic amounts of palladium (Duan, J.-P., et al., Tetrahedron Lett., 34:4019 (1993); Duan, J.-P., et al., Organometallics 14:1608 (1995)). Moinet et al., later developed an enantioselective version of this reaction but the yields were low (Tetrahedron Lett., 36:2051 (1995)).
Catalytic organometallic processes that form carbon-heteroatom bonds are far fewer in number than those which form carbon-carbon bonds. The Wacker Process (Henry, P. M., Paladium Catalysed Oxidation of Hydrocarbons, vol. 2, Reidel, Boston, (1980)), oxidative carbonylations of amines and alcohols (Applied Homogeneous Catalysis with Organometallic Compounds: A Comprehensive Handbook in Two Volumes (eds.: B. Cornils, W. A. Hermann), VCH, New York, (1984)) and the formation of arylamines and aryl ethers (Hartwig, J. F., Agnew. Chem. Int. Ed. 37:2046 (1998); Widenhoefer, R. A., et al., J. Am. Chem. Soc. 119:6787 (1997)) are a few that have been described to date.
The present invention is based upon the discovery of a rhodium catalyzed ring opening reaction of oxabenzonorbornadienes or azabicyclic compounds to produce a new carbon-oxygen bond via an intermolecular reaction with various alcohols. This reaction occurs in good yields with complete regio and diastereoselectivity and excellent enantioselectivity (e.g., eq. 1). 
In the reaction above, Z is O or NRa. This reaction will work when oxabenzonor-bornadienes or azabicyclic compounds are reacted with nitrogen nucleophiles, carboxylate nucleophiles, carbon nucleophiles or phenol nucleophiles. The invention encompasses not only the chemical reactions but also the compounds made by the reactions and the use of such compounds in the treatment of a variety of diseases and conditions.
In its first aspect, the invention is directed to a compound according to formula I: 
in which R is selected from the group consisting of:
(a) H;
(b) a C1-C6 straight or branched alkyl;
(c) a straight or branched C2-C6 alkenyl;
(d) xe2x80x94(CH2)nR1, wherein R1 is a C3-C6 aryl, optionally substituted at one or more positions with a group selected from: Cl; F; NO2; I; Br; a C1-C3 alkyl; and a C1-C3 alkoxy wherein n=0-3;
(e) xe2x80x94C(O)R2, wherein R2 is selected from the group consisting of: H; xe2x80x94(CH2)nR1, wherein R1 is as described above and n=0-3; and xe2x80x94(CH2)nC(O)R3, wherein R3 is a C1-C6 straight or branched alkyl and n=0-3;
(f) xe2x80x94C(O)(CH2)pxe2x80x94C(O)xe2x80x94Oxe2x80x94R4, wherein R4 is a straight or branched C1-C6 alkyl and wherein p=0-3;
(g) xe2x80x94Rd(CF3)j, wherein Rd is a C1-C3 straight or branched alkyl and j=1-3;
(h) xe2x80x94(CH2)jxe2x80x94TMS, wherein TMS is trimethylsilyl, and j=1-3;
X and Y are independently selected from the group consisting of H; NH2; F; Cl; Br; a C1-C3 alkyl; and a C1-C3 alkoxy;
or wherein the combination XY or YY together form a C3-C6 carbocyclic ring or a C3-C6 heterocyclic ring containing one or more heteroatoms selected from the group consisting of: O; N; and S; and
in which Z is selected from O or NRa, wherein Ra is selected from:
(i) phenyl;
(j) (O)Cxe2x80x94Oxe2x80x94Rb, wherein Rb is a straight or branched C1-C6 alkyl;
(k) xe2x80x94SO2xe2x80x94Rc, wherein Rc is selected from the group consisting of:
i) C1-C6 straight or branched alkyl;
ii) xe2x80x94(CH2)qRe, wherein q=0-3 and Re is a C3-C6 aryl, optionally substituted at one or more positions with a group selected from: Cl; F; NO2; CN;I; Br; a straight or branched C1-C3 alkyl; a C1-C3 alkoxy; and xe2x80x94C(O)Rf, wherein Rf is a C1-C3 alkyl; xe2x80x94(CH2)rCF3, wherein r=0-3;
iii) xe2x80x94Rg(CF3)s, wherein Rg is a C1-C3 straight or branched alkyl and s=1-3;
iv) xe2x80x94(CH2)sxe2x80x94TMS, wherein TMS=trimethylsilyl and s=1-3;
(l) xe2x80x94SO2xe2x80x94(CH2)qxe2x80x94Si(CH3)3 wherein q is 1-3.
Preferably, R in formula I is xe2x80x94(CH2)nR1 and R1 is a C3-C6 aryl optionally substituted at one or more positions with a group selected from: Cl; F; NO2; I; Br; a C1-C3 alkyl; and a C1-C3 alkoxy and wherein n=0-3. When Z is NRa, Ra is preferably phenyl; (O)Cxe2x80x94Oxe2x80x94Cxe2x80x94(CH3)3; xe2x80x94SO2xe2x80x94(CH2)2xe2x80x94Si(CH3)3; or xe2x80x94SO2xe2x80x94Rc, wherein Re is xe2x80x94(CH2)qRc, wherein q=0-3 and Re is a C3-C6 aryl, optionally substituted at one or more positions with a group selected from: Cl; F; NO2; CN; I; Br; a straight or branched C1-C3 alkyl; a C1-C3 alkoxy; and xe2x80x94C(O)Rf, wherein Rf is a C1-C3 alkyl; xe2x80x94(CH2)rCF3, wherein r=0-3.
The compounds of formula I described above may be prepared by reacting a compound of formula ROH with a compound of formula V: 
in which R, X, Y, and Z are as defined above. The reaction is catalyzed by [Rh(COD)Cl]2 in the presence of a phosphine ligand, preferably selected from the group consisting of: DPPF; (R)-(S)-BPPFA; and (R)-(S)-PPF-PtBu2In preferred reactions: (a) the compound made is (1R*,2R*)-acetic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl ester and ROH is acetic acid; (b) the compound made is (1R*,2R*)-propionic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl ester and ROH is propionic acid; (c) the compound made is (1R,2R)-benzoic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester and ROH is benzoic acid; (d) the compound made is (1R*,2R*)-formic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester and ROH is formic acid; (e) the compound made is (1R*,2R*)-2-methyl acrylic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester and ROH is methacrylic acid; (f) the compound made is (1R*,2R*)-malonic acid ethyl-ester (1-hydroxy-1,2-dihydro-naphthalen-2-yl) ester and ROH is ethyl malonic acid; and (g) the compound made is (1R,2R)-2-(4-bromo-phenoxy)-1,2-dihydro-naphthalen-1-ol and ROH is p-bromophenol; (h) the compound made is N-[(1R,2S)-2-methoxy-1,2-dihydrohydro-1-naphthalenyl]-4-methylbenzene-sulfonamide and ROH is MeOH; (i) the compound made is 4-methyl-N-[(1R,2S)-2-phenoxy-1,2-dihydrohydro-1-naphthalenyl]benzenesulfonamide and the ROH is phenol; (j) the compound made is (1R,2S)-1-{[(4-methylphenyl)sulfonyl]amino}-1,2-dihydrohydro-2-naphthalenyl acetate and the ROH is acetic acid; (k) the compound made is (1R,2S)-1-{[(4-methylphenyl)-sulfonyl]amino}-1,2-dihydro-2-naphthalenyl benzoate and the ROH is benzoic acid; (1) the compound made is (1R,2S)-1-{[(4-methylphenyl)sulfonyl]amino}-1,2-dihydro-2-naphthalenyl private and the ROH is pivalic acid; (m) the compound made is N-[(1R,2S)-2-methoxy-1,2-dihydro-1-naphthalenyl]-2-(trimethylsilyl)ethanesulfonamide and ROH is methanol.
In a second aspect the invention is directed to a compound according to formula II: 
in which R is selected from the group consisting of:
(a) a C1-C6 straight or branched alkyl;
(b) xe2x80x94(CH2)qR5, wherein q=0-3 and R5 is a C3-C6 aryl optionally substituted at one or more positions with a group selected from: a straight or branched C1-C3 alkyl; a C1-C3 alkoxy; Br; I; Cl; CN; F; NO2; (CH2)rCF3, wherein r=0-3; and xe2x80x94C(O)R6, wherein R6 is a C1-C3 alkyl;
(c) xe2x80x94R7(CF3)s, wherein R7 is a C1-C3 straight or branched alkyl and s=1-3;
(d) xe2x80x94(CH2)sxe2x80x94TMS, wherein TMS=trimethylsilyl and s=1-3;
X and Y are independently selected from the group consisting of H; NH2; F; Cl; Br; a C1-C3 alkyl; and a C1-C3 alkoxy;
or wherein the combination XY or YY together form a C3-C6 carbocyclic ring or a C3-C6 heterocyclic ring containing one or more heteroatoms selected from the group consisting of: O; N; and S; and
in which Z is selected from O or NRa, wherein Ra is selected from:
(e) phenyl;
(f) (O)Cxe2x80x94Oxe2x80x94Rb, wherein Rb is a straight or branched C1-C6 alkyl;
(g) xe2x80x94SO2xe2x80x94Rc, wherein Rc is selected from the group consisting of:
i) C1-C6 straight or branched alkyl;
ii) xe2x80x94(CH2)qRe, wherein q=0-3 and Re is a C3-C6 aryl, optionally substituted at one or more positions with a group selected from: Cl; F; NO2; CN;I; Br; a straight or branched C1-C3 alkyl; a C1-C3 alkoxy; and xe2x80x94C(O)Rf, wherein Rf is a C1-C3 alkyl; xe2x80x94(CH2)rCF3, wherein r=0-3;
iii) xe2x80x94Rg(CF3)s, wherein Rg is a C1-C3 straight or branched alkyl and s=1-3;
iv) xe2x80x94(CH2)sxe2x80x94TMS, wherein TMS=trimethylsilyl and s=1-3;
(h) xe2x80x94SO2xe2x80x94(CH2)qxe2x80x94Si(CH3)3 wherein q is 1-3.
Preferably, R in formula II is xe2x80x94(CH2)qR5 wherein q=0-3 and R5 is a C3-C6 aryl optionally substituted at one or more positions with a group selected from: a straight or branched C1-C3 alkyl; a C1-C3 alkoxy; I; Cl; CN; F; NO2; xe2x80x94(CH2)rCF3, wherein r=0-3; and xe2x80x94C(O)R6, wherein R6 is a C1-C3 alkyl.
The compounds of formula II described above may be prepared by reacting a compound of formula ROH with a compound of formula V: 
wherein R, X, Y, and Z are as defined above in connection with formula II and in which the reaction is catalyzed by [Rh(COD)Cl]2 in the presence of a phosphine ligand, preferably (S)-(R)-PPF-PtBu2. In preferred reactions: (a) the compound made is (1S,2S)-2-methoxy-1,2-dihydro-naphthalen-1-ol, and ROH is methanol; (b) the compound made is (1S,2S)-2-(ethoxy)-1,2-dihydro-naphthalen-1-ol, and ROH is ethanol; (c) the compound made is (1S,2S)-2-isopropoxy)-1,2-dihydro-naphthalen-1-ol and ROH is isopropanol; (d) the compound made is (1S,2S)-2-1-propenyloxy)-1,2-dihydro-naphthalen-1-ol, and ROH is allyl alcohol; (e) the compound made is (1S,2S)-2-(2-trimethylsilyl-ethoxy)-1,2-dihydro-naphthalen-1-ol, and ROH is trimethylsilyl-ethanol; (f) the compound made is (1S,2S)-2-benzyloxy-1,2-dihydro-naphthalen-1-ol, and ROH is benzylalcohol; (g) the compound made is (1S,2S)-2-4-methoxybenzyloxy-1,2-dihydro-naphthalen-1-ol, and ROH is anisylalcohol; (h) the compound made is (1S,2S)-2-(2,2,2-trifluoro-ethoxy)-1,2-dihydro-naphthalen-1-ol, and ROH is trifluoroethanol; (i) the compound made is (1S,2S)-2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-1,2-dihydro-naphthalen-1-ol and ROH is hexafluoro-isopropanol; (j) the compound made is (1S,2S)-6,7-difluoro-2-methoxy-1,2-dihydro-naphthalen-1-ol and ROH is methanol; (k) the compound made is (lS,2S)-6-methoxy-5,6-dihydro-naphtho[2,3-d][1,3]dioxol-5-ol and ROH is methanol; (l) the compound made is (1S,2S)-6,7-dibromo-2-methoxy-5,8-dimethyl-1,2-dihydro-naphthalen-1-ol and ROH is methanol; (m) the compound made is (1S,2S)-2-phenoxy-1,2-dihydro-naphthalen-1-ol and ROH is phenol; (n) the compound made is (1S,2S)-2-(4-nitrophenoxy)-1,2-dihydro-naphthalen-1-ol and ROH is 4-nitrophenol; (o) the compound made is (1S,2S)-2-(4-cyanophenoxy)-1,2-dihydro-naphthalen-1-ol and ROH is 4-cyanophenol; (p) the compound made is (1S,2S)-2-(4-acylphenoxy)-1,2,-dihydro-naphthalen-1-ol and ROH is 4-hydroxyaceto-phenone; (q) the compound made is (1S,2S)-2-(4-trifluoromethylphenoxy)-1,2,-dihydro-naphthalen-1-ol and ROH is 4-trifluoromethylphenyl; (r) the compound made is (1S,2S)-2-(4-fluorophenoxy)-1,2-dlhydro-naphthalen-1-ol and ROH is 4-fluorophenol; (s) the compound made is (1S,2S)-2-(4-chlorophenoxy)-1,2-dihydro-naphthalen-1-ol and ROH is 4-chlorophenol; (t) the compound made is (1S,2S)-2-(4-iodophenoxy)-1,2-dihydro-naphthalen-1-ol and ROH is 4-iodophenol; (u) the compound made is (1S,2S)-2-(4-methylphenoxy)-1,2-dihydro-naphthalen-1-ol and ROH is p-cresol; (v) the compound made is (1S,2S)-2-(4-methoxyphenoxy)-1,2-dihydro-naphthalen-1-ol and ROH is 4-methoxyphenol; and (w) the compound made is (1S,2S)-2-(2-bromophenoxy)-1,2-dihydro-naphthalen-1-ol and ROH is 2-bromophenol. When Z is NRa, Ra is preferably phenyl; (O)Cxe2x80x94Oxe2x80x94Cxe2x80x94(CH3)3; 
The invention is also directed to a compound according to formula III: 
wherein TBDMSO is a tert-butyldimethylsiloxy group, and R, X, and Y are as defined in above in connection with formula I. These compounds may be made by preparing a compound of formula I according to the process described above and then reacting the compound formed with a salt of tert-butyldimethylsilylic acid. Preferably, the compound formed is (1R*,2R*)-malonic acid (1-tert-butyldimethylsiloxy-1,2-dihydro-naphthalen-2-yl) ester ethyl ester and ROH is tert-butyldimethylsilylic acid.
In another aspect, the invention is directed to a compound according to formula IV: 
a) in which R8 is H or CH3;
b) t=0-3
c) R9 is a C3-C6 aryl optionally substituted at one or more positions with a group selected from: a C1-C3 alkyl; a C1-C3 alkoxy; Cl; F; NO2; and CF3; or R9 together with N form a ring structure selected from: a phthalamide ring; a pyrrolidine ring; a piperidine ring; a tetrahydroquinoline ring; and an indole ring; said ring structure being optionally substituted at one or more positions with a group selected from: a C1-C3 alkyl; a C1-C3 alkoxy; Cl; F; NO2; and CF3;
d) X and Y are independently selected from the group consisting of H; NH2; F; Cl; Br; a C1-C3 alkyl; and a C1-C3 alkoxy; or wherein the combination XY or YY together form a C3-C6 carbocyclic ring or a C3-C6 heterocyclic ring containing one or more heteroatoms selected from the group consisting of: O; N; and S;
e) Z is selected from O or NRa, wherein Ra is selected from:
(i) a straight or branched C1-C6 alkyl;
(ii) phenyl;
(iii) (O)Cxe2x80x94Oxe2x80x94Rb, wherein Rb is a straight or branched C1-C6 alkyl;
(iv) xe2x80x94SO2xe2x80x94Rc, wherein Rc is an unsubstituted phenyl or a phenyl substituted with a C1-C3 alkyl or NO2; and
(v) xe2x80x94SO2xe2x80x94(CH2)qxe2x80x94Si(CH3)3 wherein q is 1-3; and
f) when Z is O, R10 is H; when Z is NRa, R10 is either H or CH3.
Preferably, R8 in formula IV is H and R9 together with N form a ring selected from the group consisting of a phthalamide ring; a pyrrolidine ring; a piperidine ring; a tetrahydroquinoline ring; and an indole ring; the ring being optionally substituted at one or more positions with a group selected from: a C1-C3 alkyl; a C1-C3 alkoxy; Cl; F; NO2; and CF3. When Z is NRa, Ra is preferably methyl; 
The compounds of formula IV described above may be prepared by reacting a compound of formula R9xe2x80x94(CH2)tNHR8 with a compound of formula V 
in which R8, R9, t, X, Y, and Z are as defined above in connection with compounds of formula IV and the reaction is catalyzed by [Rh(COD)Cl]2 in the presence of a phosphine ligand; preferably selected from the group consisting of: DPPF; (R)-(S)-BPPFA; and (R)-(S)-PPF-PtBu2. When Z is NRa, the reaction will produce a product in which R10 is H. A subsequent reaction may be used to convert R10 to a methyl as set forth in the Examples section below. Most typically, the process will be used to produce products in which R9 together with N form a ring selected from the group consisting of: a phthalamide ring; a pyrrolidine ring; a piperidine ring; a tetrahydroquinoline ring; and an indole ring; said ring structures being optionally substituted at one or more positions with a group selected from: a C1-C3 alkyl; a C1-C3 alkoxy; Cl, F; NO2; and CF3. In preferred reactions: (a) the compound made is (1R,2R)-2-(1-hydroxy-1,2-dihydro-naphthalen-2-yl) isoindole-1,3-dione and R9xe2x80x94(CH2)sNHR8 is phthalimide; (b) the compound made is (1R*,2R*)-2-pyrroldin-1-yl-1,2-dihydro-naphthalen-1-ol and R9xe2x80x94(CH2)sNHR8 is pyrrolidine, (c) the compound made is (1R*,2R*)-2-piperidin-1-yl-1,2-dihydro-naphthalen-1-ol and R9xe2x80x94(CH2)sNHR8 is piperidine; (d) the compound made is (1R,2R)-2-(3,4-dihydro-2H-quinolin-1-yl)-1,2-dihydro-naphthalen-1-ol and R9xe2x80x94(CH2)sNHR8 is tetrahydroisoquin-oline; (e) the compound made is (1R,2R)-2(methyl-phenyl-amino)-1,2-dihydro-naphthalen-1-ol and R9xe2x80x94(CH2)sNHR8 is N-methylaniline; (f) the compound made is (1R*,2R*)-2-benzylamino-1,2-dihydro-naphthalen-1-ol and R9xe2x80x94(CH2)sNHR8 is benzyl-amine; (g) the compound made is (1R*,2R*)-2-(4-methoxy-benzylamino)-1,2-dihydro-naphthalen-1-ol and R9xe2x80x94(CH2)sNHR8 is p-methoxybenzylamine; and (h) the compound made is (1R,2R)-2-indol-1-yl-1,2-dihydro-naphthalen-1-ol and R9xe2x80x94(CH2)sNHR8 is indole; (i) the compound made is N-[1R,2R)-2(1-pyrrolidinyl)-1,2-dihydronaphthalenyl]-4-methylbenzenesulfonamide and the R9xe2x80x94(CH2)tNHR8 is pyrrolidine; (j) the compound made is N-[(1R,2S)-2-(1H-indol-1-yl)-1,2-dihydro-1-naphthalenyl]-4-methylbenzenesulfonamide and the R9xe2x80x94(CH2)tNHR8 is indole; (k) the compound made is N-[(1R,2S)-2-(3,4-dihydro-2(1H)-isoquinolinyl)-1,2-dihydro-1-naphthalenyl]-4-methylbenzenesulfonamide and the R9xe2x80x94(CH2)tNHR8 is tetrahydroisoquinoline; (l) the compound made is N-[(1R,2S)-2-(3,4-dihydro-1(2H)-quinolinyl)-1,2-dihydro-1-naphthalenyl]-4-methylbenzenesulfonamide and the R9xe2x80x94(CH2)tNHR8 is tetrahydroquinoline; (m) the compound made is 4-methyl-N-[(1R,2S)-2-(1-piperidinyl)-1,2-dihydro-1-naphthalenyl]-benzenesulfonamide and the R9xe2x80x94(CH2)tNHR8 is piperidine.
The invention also encompasses seven other processes. In the first (1S,2S)-N-(1-hydroxy-1,2-dihydro-naphthalen-2-yl)-benzene sulfonamide is formed by reacting oxabenzonorbornadiene with benzenesulfonamide. In the second, (1S*,2R*)-2-(hydroxy-1,2-dihydro-naphthalen-2-yl)malonic acid dimethyl ester is formed by reacting oxabenzonorbornadiene with dimethyl malonate. Both reactions are catalyzed by [Rh(COD)Cl]2 in the presence of a phosphine ligand. In the third, the compound of formula VI is formed by reacting a compound of formula IV, which is produced as described above in connection with formation of compounds of formula IV, with iodomethane. In preferred reactions, the compound made is N,4-dimethyl-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]benzenesulfonamide. In the fourth, the compound of formula VII is formed by reacting compound of formula VI with hydrogen in the presence of palladium catalyst. The compound made is N,4-dimethyl-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2,3,4-tetrahydro-1-naphthalenyl]benzenesulfonamide. In the fifth, the compound of formula VIII is formed by reacting the compound of formula VII with sodium borohydride. The compound made using this reaction is (1R,2S)-N-methyl-2-(1-pyrrolidinyl)-1,2,3,4-tetrahydro-1-naphthalenamine. In the sixth, the compound of formula IX is formed by reacting a compound of formula IV which is produced as described above in connection with formation of compounds of formula IV, with iodomethane. The compound made using this reaction is N-methyl-4-nitro-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]benzenesulfonamide. In the seventh, the compound of formula X is formed by reacting a compound of formula I which is produced as described above in connection with formation of compounds of formula I, with iodomethane. The compound made using this reaction is (1R,2S)-1-{methyl[(4-methylphenyl)sulfonyl]amino}-1,2-dihydro-2-naphthalenyl acetate. 
Overall, the most preferred compounds of the invention are:
a) (1S,2S)-2-methoxy-1,2-dihydro-naphthalen-1-ol;
b) (1S,2S)-2-(ethoxy)-1,2-dihydro-naphthalen-1-ol;
c) (1S,2S)-2-(isopropoxy)-1,2-dihydro-naphthalen-1-ol;
d) (1S,2S)-2-(1-propenyloxy)-1,2-dihydro-naphthalen-1-ol;
e) (1S,2S)-2-(2-trimethylsilyl-ethoxy)1,2-dihydro-naphthalen-1-ol;
f) (1S,2S)-2-benzyloxy-1,2-dihydro-naphthalen-1-ol;
g) (1S,2S)-2-(4-methoxybenzyloxy)-1,2-dihydro-naphthalen-1-ol;
h) (1S,2S)-2-(2,2,2-trifluoro-ethoxy)-1,2-dihydro-naphthalen-1-ol;
i) (1S,2S)-2-(2,2,2-trifluoro-1-trifluoromethyl-ethoxy)-1,2-dihydro-naphthalen-1-ol;
j) (1S,2S)-6,7-difluoro-2-methoxy-1,2-dihydro-naphthalen-1-ol;
k) (1S,2S)-6-methoxy-5,6-dihydro-naphthol[2,3-d][1,3]dioxol-5-ol;
l) (1S,2S)-6,7-dibromo-2-methoxy-5,8-dimethyl-1,2-dihydro -naphthalen-1-ol;
m) (1R*,2R*)-acetic acid 1,-hydroxy-1,2-dihydro-naphthalen-2-yl-ester;
n) (1R*,2R*)-propionic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester;
o) (1R,2R)-benzoic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester;
p) (1R*,2R*)-formic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester;
q) (1R*,2R*)-2-methyl acrylic acid 1-hydroxy-1,2-dihydro-naphthalen-2-yl-ester;
r) (1R*,2R*)-malonic acid ethyl ester (1-hydroxy-1,2-dihydro-naphthalen-2-yl) ester;
s) (1R*,2R*)-malonic acid (1-tert-butylbimethylsiloxy-1,2-dihydro-naphthalen-2-yl) ethyl ester;
t) (1S*,2S*)4-tert-butyldimethylsiloxy-1,4-dihydro-naphthalen-2-yl) acetic acid ethyl ester;
u) (1R,2R)-2-(1-hydroxy-1,2-dihydro-naphthalen-2-yl)-isoindole-1,3-dione;
v) (1S,2S)-N-(1-hydroxy-1,2-dihydro-naphthalen-2-yl)-benzene sulfonamide;
w) (1R*,2R*)-2-pyrrolidin-1-yl-1,2-dihydro-naphthalen-1-ol;
x) (1R*,2R*)-2-piperidin-1-yl-1,2-dihydro-naphthalen-1-ol;
y) (1R,2R)-2-(3,4-dihydro-2H-quinolin-1-yl)-1,2-dihydro-naphthalen-1-ol;
z) (1R,2R)-2-(methyl-phenyl-amino)-1,2-dihydro-naphthalen-1-ol;
aa) (1R*,2R*)-2-benzylamino-1,2-dihydro-naphthalen-1-ol;
bb) (1R*,2R*)-2-(4-methoxy-benzylamino)-1,2-dihydro-naphthalen-1-ol;
cc) (1R,2R)-2-indol-1-yl-1,2-dihydro-naphthalen-1-ol;
dd) (1S*,2R*)-2-(hydroxy-1,2-dihydro-naphthalen-2-yl)malonic acid dimethyl ester;
ee) (1S,2S)-2-phenoxy-1,2-dihydro-naphthalen-1-ol;
ff) (1S,2S)-2-(4-nitrophenoxy)-1,2-dihydro-naphthalen-1-ol;
gg) (1S,2S)-2-(4-cyanophenoxy)-1,2-dihydro-naphthalen-1-ol;
hh) (1S,2S)-2-(4-acylphenoxy)-1,2-dihydro-naphthalen-1-ol;
ii) (1S,2S)-2-(4-trifluoromethylphenoxy)-1,2-dihydro-naphthalen-1-ol;
jj) (1S,2S)-2-(4-fluorophenoxy)-1,2-dihydro-naphthalen-1-ol;
kk) (1S,2S)-2-(4-chlorophenoxy)-1,2-dihydro-naphthalen-1-ol;
ll) (1S,2S)-2-(4-iodophenoxy)-1,2-dihydro-naphthalen-1-ol;
mm) (1R,2R)-2-(4-bromo-phenoxy)-1,2-dihydro-naphthalen-1-ol;
nn) (1S,2S)-2-(4-methylphenoxy)-1,2-dihydro-naphthalen-1-ol;
oo) (1S,2S)-2-(4-methoxyphenoxy)-1,2-dihydro-naphthalen-1-ol;
pp) (1S,2S)-2-(2-bromeophenoxy)-1,2-dihydro-naphthalen-1-ol;
qq) 4-methyl-N-[(1R,2S)-2-(1-piperidinyl)-1,2-dihydro-1-naphthalenyl]benzenesulfonamide;
rr) N-[(1R,2S)-2-(3,4-dihydro-1(2H)-quinolinyl)-1,2-dihydro-1-naphthalenyl]-4-methylbenzenesulfonamide;
ss) N-[(1R,2S)-2-(3,4-dihydro-2(1H)-isoquinolinyl)-1,2-dihydro-1-naphthalenyl]-4-methylbenzenesulfonamide;
tt) N-[(1R,2S)-2-(1H-indol-1-yl)-1,2-dihydro-1-naphthalenyl]-4-methylbenzenesulfonamide;
uu) (1R,2S)-2-methoxy-N-phenyl-1,2-dihydro-1-naphthalenamine;
vv) tert-butyl (1R,2S)-2-methoxy-1,2-dihydro-1-naphthalenylcarbamate;
ww) N-[(1R,2S)-2-methoxy-1,2-dihydro-1-naphthalenyl]-2-(trimethylsilyl)ethanesulfonamide;
xx) N,4-dimethyl-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2,3,4-tetrahydro-1-naphthalenyl]benzenesulfonamide;
yy) N,4-dimethyl-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]benzenesulfonamide;
zz) N-hydroxy-4-({methyl[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]amino}sulfonyl)-N-oxobenzenaminium;
aaa) N-methyl-4-nitro-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]benzenesulfonamide;
bbb) (1R,2S)-N-methyl-2-(1-pyrrolidinyl)-1,2,3,4-tetrahydro-1-naphthalenamine;
ccc) N-[(1R,2S)-2-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl]-4-methylbenzenesulfonamide;
ddd) N-[(1R,2S)-2-methoxy-1,2,3,4-tetrahydro-1-naphthalenyl]-4-methylbenzenesulfonamide;
eee) 4-methyl-N-[(1R,2S)-2-phenoxy-1,2,3,4-tetrahydro-1-naphthalenyl]benzenesulfonamide;
fff) (1R,2S)-1-{[(4-methylphenyl)sulfonyl]amino)}-1,2,3,4-tetrahydro-2-naphthalenyl acetate;
ggg) (1R,2S)-1-{[(4-methylphenyl)sulfonyl]amino}-1,2-dihydro-2-naphthalenyl benzoate;
hhh) (1R,2S)-1-{[(4-methylphenyl)sulfonyl]amino}-1,2-dihydro-2-naphthalenyl pivalate;
iii) N-[(1R,2S)-2-methoxy-1,2-dihydro-1-naphthalenyl]-2-(trimethylsilyl)ethanesulfonamide;
jjj) tert-butyl (1R,2S)-2-methoxy-1,2-dihydro-1-naphthalenylcarbamate; and
kkk) 4-nitro-N-[(1R,2S)-2-(1-pyrrolidinyl)-1,2-dihydro-1-naphthalenyl]benzenesulfonamide.
Any of the compounds described above may be incorporated into a pharmaceutical preparation and administered to a patient in an amount effect for relieving one or more symptoms associated with a variety of diseases and conditions. Among the diseases that may be treated are Parkinson""s disease, cancer and AIDS.
The present invention is based upon the discovery of a new process for the formation of enantiomerically enriched compounds containing the hydronaphthalene ring structure. The process involves reacting an aza- or oxabenzonorbornadiene compound with a nucleophile in the presence of a rhodium catalyst and a phosphine ligand. Detailed procedures for the formation of precursor compounds and their use in reactions are set forth in the Examples section below. Preferred nucleophiles are alcohols, phenols, amines, and stabilized carbanions such as malonates and malonate equivalents. In cases where simple aliphatic amines are used, reactions should be performed in the presence of a tertiary amine hydrochloride. This is not necessary for other types of amines. When carboxylic acids are used, reactions should be carried out in the presence of a tertiary amine, e.g., triethylamine. Alternatively, the sodium or potassium salt of the carboxylic acid may be reacted in the presence of the hyrochloride of a tertiary amine, e.g in the presence of triethylamine hydrochloride. It has been found that carboxylate ring-opened products can be made to undergo a subsequent transformation to produce 1,4-disubstituted dihyronaphthalenes. This is accomplished by an SN2xe2x80x2 addition of nucleophiles under catalytic or non-catalytic conditions to the allyl acetate functionality. For an example of the conversion of (1R*,2R*)-malonic acid (1-tert-butyldimethylsiloxy-1,2-dihydro-naphthalen-2-yl) ester ethyl ester to 1S*,2S*)-(4-Tert-butyldimethylsiloxy-1,4-dihydro-naphthalen-2-yl) acetic acid ethyl ester see the Examples section below.
The preferred catalyst is [Rh(COD)Cl]2 and, depending upon the particular product desired, preferred ligands are DPPF or a chiral analogue of DPPF, (R)-(S)-BPPFA; (R)-(S)-PPF-PtBu2 and (S)-(R)-PPF-PtBu2. The ligands may be prepared by any process described in the literature (see, e.g., Togni et al., J. Am. Chem. Soc. 116:4062 (1994)). Reactions maybe carried out using trifluoroethanol (TFE) or tetrahydrofuran (THF) as solvents under an inert atmosphere, preferably of nitrogen. The reaction temperature should typically be at least 60xc2x0 C. and preferably about 80xc2x0 C.
The compounds formed may be incorporated into a pharmaceutical composition and used in the treatment of a variety of diseases and conditions. Specifically, the compounds may be used in the treatment of Parkinson""s disease, cancers, and AIDS. The total daily dosage of compound administered to a patient should be at least the amount required to reduce or eliminate one or more symptoms associated with the condition being treated. For example, in the treatment of Parkinson""s disease, sufficient agent should be administered to reduce the severity or frequency of tremors or other movement disorders associated with the disease. In treating cancers, agents should typically be given at a dosage sufficient to reduce tumor size or at a dosage sufficient to reduce the total number of cancerous cells in a patient. The actual dose selected for an individual patient will be determined by the attending physician based upon clinical conditions and using methods well known in the art. Agents may be provided in either a single or multiple dosage regimen, e.g., a patient may be administered compounds twice a day.
Any route of administration and dosage form is compatible with the present invention, and therapeutic agents may be administered as either the sole active ingredient or in combination with other therapeutically active drugs. Routes of delivery compatible with the invention include parenteral, peroral, internal, pulmonary, rectal, nasal, vaginal, lingual, transdermal, intravenous, intraarterial, intramuscular, intraperitoneal, intracutaneous, and subcutaneous routes. Specific dosage forms that may be used include tablets, pills, capsules, powders, aerosols, suppositories, skin patches, parenterals, and oral liquids, including oil aqueous suspensions, solutions, and emulsions. Sustained release dosage forms may also be used. All dosage forms may be prepared using methods that are standard in the art (see, e.g., Remington""s Pharmaceutical Sciences, 16th ed., A. Oslo, editor, Easton Pa. (1980)).
Therapeutic agents may be used in conjunction with any of the vehicles and excipients only employed in pharmaceutical preparations, e.g., talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous solvents, oils, paraffin derivatives, glycols, etc. Coloring and flavoring agents may also be added to preparations designed for oral administration. Solutions can be prepared using water or physiologically compatible organic solvents such as ethanol, 1,2-propylene glycol, polyglycols, dimethyl sulfoxide, fatty alcohols, triglycerides, partial esthers of glycerine, and the like. Parenteral compositions containing compounds may be prepared using conventional techniques and include sterile isotonic saline, water, 1,3-butane diol, ethanol, 1,2-propylene glycol, polyglycols mixed with water, Ringer""s solution, etc.
If desired, a patient may be initially given a relatively low dose of therapeutic agent in order to determine whether any adverse side effects are experienced. This may be particularly important in cases where a patient is taking other medications or has clinical characteristics that suggest that they may not be able to tolerate high drug dosages. If adverse side effects are not experienced by a patient, dosage may be gradually increased until a satisfactory alleviation of symptoms is achieved. For example, the dosage given to a patient with AIDS may be increased until blood counts return to a normal or more normal level.